Reprinted with the kind permission of Simmaron Foundation.
By Cort Johnson
Three MEGA chronic fatigue syndrome (ME/CFS) projects (The OMF’s Severe ME/CFS Big Data project, NIH’s Clinical Center Study, The UK’s Grand Challenge) were recently discussed on Health Rising, but another “mega” project exists.
They all have some similarities. Like the others, the mega project underway at the Center for Infection and Immunity (CII) is attempting to get at the molecular roots of chronic fatigue syndrome (ME/CFS). Like the others it’ll be searching through vast amounts of data in an attempt to uncover the unique biological signature(s).
Like the Open Medicine Foundation and NIH Clinical Center projects, some of the technology has been developed in-house. We’re blessed with the attention of some of the most innovative researchers in the world.
Let’s take advantage of a recent talk by Simmaron Researcch Foundation Scientific Board member Mady Hornig in Sweden and check out the CII’s big plans for ME/CFS. (A transcript of the talk is provided on the striking, new Microbe Discovery website).
We learned recently that the internationally renowned Ian Lipkin is all in for chronic fatigue syndrome (ME/CFS); that his bucket list includes just two diseases: ours and autism. Mady Hornig certainly didn’t skimp on her vision for ME/CFS at the talk either; she wants to create a Center of Excellence for ME/CFS at the CII, and hopes that the large array of studies the Center is engaged in will lay the foundation for that.
You can’t have research centers without funding, though. The NIH has been very responsive recently, and the big Clinical Center study is very exciting, but extramural funding is where it’s at and little money thus far has flowed to outside researchers. Last year Ian Lipkin and Mady Hornig in one of the weirdest grant awards ever received money for sampling but no money for analysis (?) – and then had to drop in 500 K in to complete their sampling. It’s no wonder then that Mady Hornig (six months ago) referred to a “crisis” in funding. This, of course, is a crisis that’s been present for over 20 years.
Times are changing, though, and hopefully we’ll get some good news soon about the Trans NIH Working Group’s”strategy to reinvent ME/CFS at the NIH.
Even with this dearth of federal funding the CII, with the help of the Chronic Fatigue Initiative (funding metabolomics, proteomics, immune signatures, pathogen discovery projects), the Microbe Discovery Project, the (microbiome), the Stanford program (pathogens), the Simmaron Research Foundation (spinal fluid) and others, has put together a megaproject – a diverse, multidimensional attack focused on getting at the molecular underbelly of ME/CFS.
Check out the different stabs at ME/CFS the group is taking.
Dr. Montoya said last year to prepare for some exciting results in the pathogen study.
The Pathogen Slant – in a very large study, the CII using PCR, Mass Tag PCR (developed in Lipkin’s laboratory) and high throughput will scan for 1.7 million agents in, if I’m reading it right, 800 patients and controls. In his Spring 2015 and 2016 newsletters, Dr. Montoya said to expect some exciting results. They’re looking at viruses, bacteria, and for the first time ever in ME/CFS, fungi.
The Gut Plus Slant – (n=100) -The CII expects their microbiome analysis of the bacteria and fungi in gut will tell them a lot about immune functioning. It turns out that no less than 60% of our immune cells travel through and get altered by bacterial metabolites in the gut before they make it to the blood. They’re also looking at the throat area to see what this common collection point for pathogens might tell them. The CII has finished their first analyses of their initial gut study: the results were apparently good enough for the team to expand their study and begin taking multiple samples from the same patient over time.
It’s this kind of rigorous, dogged, longitudinal approach to ME/CFS – which no one by the way as ever done before – that they hope will put them first in line for a Center of Excellence. I don’t think anyone, ever, has watched the immune and microbiome systems over the length of time (12-18 months) the CII is. It would be very hard, indeed, to discount any pattern that consistently showed up over that period of time.
Plus, they’re building quite a biobank of samples at the same time. The CII will surely be at the top of the NIH’s list of potential ME/CFS research consortiums.
The Autoimmune Slant – Autoantibodies could conceivably be behind everything that happens in ME/CFS. The CII will be looking for autoantibodies to human cells and pathogens including viruses, bacteria and fungi. This will allow them to dig up evidence of past infections that may have triggered ME/CFS. Their search will also include those adrenergic autoantibodies recently found in POTS patients that dysregulate their heart rates.
The RNA Seq / miRNA – Gene expression Slant – Gene expression tells us which genes are doing what. This study will determine what’s happening with the immune genes in ME/CFS. Right now we might guess they’ll see increased immune gene expression early in the disease and reduced gene expression.
Since studies have shown that unique patterns of gene expression or genetics predispose people to prolonged courses of illness after an infection, this study is ripe with promise. (If I’m reading this right a paper should be out in the not too distant future.)
The CII could end up identifying:
1. pathogens that kick off the illness
2. a pattern of gene expression that makes ME/CFS patients particularly vulnerable to that pathogen and
3. the autoimmune reaction that grew out of an inadequate immune response that failed to quickly dispatch the pathogen.
Itraq / MRM Metabolomics ( amino acids, kynurenine, serotonin) Slant – The CII is particularly interested in how metabolomics (the search for metabolites in the blood) may be able to tell them what’s happening in gut.
The L-tryptophan and the kynurenine pathway is a particular focus. L-tryptophan should metabolize into serotonin, a feel good chemical involved in sleep, sex drive, vigilance and mood regulation. L-tryptophan, however, can also be captured by the kynurenine pathway which metabolizes it into some nasty products (bye-bye good feelings). The kynurenine pathway has popped up in an array of neurological and neuropsychiatric diseases.
Dr. Hornig noted their metabolomic analyses suggest the kynurenine pathway is alive and well in some ME/CFS patients. In a prior talk, she reported that their early data suggests that a subset of people with ME/CFS with low serotonin have increased immune activation ( IL-1 beta, TNF alpha, IL-12p40, and L-17F) as well.
Interestingly, interferon gamma (IFN-y) (see below) – an antiviral and proinflammatory activating cytokine, and TNF-a – a powerful pro-inflammatory cytokine, both of which may have become activated early in the disease, both push tryptophan metabolism into the kynurenine pathway.
Dr. Hornig said they were “very keen” to understand tryptophan’s role in ME/CFS.
Cytokine and Immune Arrays Slant – They are or will be examining a wide array of cytokine levels over time to pluck out the most consistent contributors to ME/CFS. Many people are interested in the role the autonomic nervous system plays in ME/CFS but the Lipkin/Hornig group may be the first to examine the role the immune system plays in causing the ANS issues and/or problems with orthostatic intolerance. Allergy related cytokines (IL-4, IL-13, IL-17A, IL-10, Eotaxin) that can affect histamine production and alter blood pressure have popped up in their studies (and eotaxin has popped in other studies).
Histamine, of course, can have devastating effects of blood pressure and circulation. Dr. Hornig believes some of the “systemic fatigue” in chronic fatigue syndrome could originate here.
The Spinal Fluid Slant – The Simmaron/CII study was not only the first study ever to document similar immune changes in the blood and spinal fluid, but it also introduced two new subsets; Dr. Peterson’s typical / atypical patietnts. Dr. Lipkin was so high on expanding the spinal fluid study that he flew out to Lake Tahoe for the first time in 20 years to rally support for it.
An expanded Simmaron/CII spinal fluid study with more participants and more testing is underway. Should testing reveal similar findings in the spinal fluid and the blood again, a powerful message would be sent that ME/CFS is a immune disease.
People with shorter duration illnesses could possibly benefit from antibodies to IL-17A or interferon gamma that could reduce their hyperactive response to these cytokines. Many commercial antibodies, in fact, are now available. If Hornig/Lipkin can validate upregulated IL-17A or interferon gamma is present those treatments could become available to people with ME/CFS.
For the longer duration patients Dr. Hornig suggested that increasing the immune response by using Ampligen or [ an IL-1 receptor antagonist could be helpful.
The immune system doesn’t just poop out in the longer duration patients – it kind of goes bananas. An immune networking comparison in short vs longer duration patients suggested a very focused and active immune network existed in short duration patients. In the longer duration patients, though, a much more complex immune network featuring many down-regulated immune pathways was present. It’s the stark a portrayal of these two subsets that I’ve seen.
These big data studies may result in some surprises popping out.
Biomarker? – Despite the fact that interferon gamma levels were not particularly high they were incredibly predictive of short duration patients. That suggested, as Jarred Younger’s and Gordon Broderick’s work has suggested, that context is the key. It’s possible that increased IFN-y in the context of ME/CFS has unexpectedly strong effects.
Remember This – A big surprise in the longer duration patients spinal fluid was the almost complete disappearance of IL-6, a cytokine needed for memory storage and retrieval. The IL-1 receptor- antagonist (IL-1ra) was very low as well. That was an intriguing finding given that (a) the network analysis suggested that IL-1ra was a key down-regulating element in ME/CFS and (b) drugs such as Anakinra could boost it back up – and presumably stop the central nervous system down-regulation.
The Center for Infection and Immunity, led by Dr. Lipkin and Dr. Hornig, is engaged – largely thanks to the Chronic Fatigue Initiative as well as the Simmaron Research Foundation – in the third mega study of ME/CFS under way. Among the unique elements of this project are it’s continuing spinal fluid component, it’s strong focus on the gut and the kynurenine pathway, and it’s long term longitudinal study that could prove pivotal in validating ME/CFS as a disease.
The CII’s strong blood immune and spinal fluid studies last year probably helped the NIH agree to reinvigorate ME/CFS research. Hopefully, that’s just beginning of the role the Center will play in deciphering ME/CFS. Boasting one of the most extensive research efforts on ME/CFS, it surely it’s a strong candidate to be one of the ME/CFS research consortiums we hope will get funding.